上海交通大学学报（医学版）

上海交通大学学报（医学版）

• 论著（基础研究） • 上一篇    下一篇

新型CDK2-cyclinA2小分子抑制剂的设计、合成及生物学活性研究

卫迎庆1，张璐2，胡雨彤1，张健1，沈瑛1   

  1. 1. 上海交通大学 基础医学院，上海 200025；2. 大连医科大学药学院，大连 116044
  • 出版日期:2017-03-28 发布日期:2017-03-30
  • 通讯作者: 张健，电子信箱：jian.zhang@sjtu.edu.cn。
  • 作者简介:卫迎庆(1989—)，男，硕士生；电子信箱：wei_yingqing@163.com。

Novel small-molecule CDK2-cyclinA2 inhibitors: design, synthesis, and biological evaluation

WEI Ying-qing1, ZHANG Lu2, HU Yu-tong1, ZHANG Jian1, SHEN Ying1   

  1. 1. Basic Medicine Faculty of Shanghai Jiao Tong University, Shanghai 200025, China; 2.College of Pharmacy, Dalian Medical University, Dalian 116044, China
  • Online:2017-03-28 Published:2017-03-30

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摘要：

目的 ·设计、合成新型CDK2-cyclinA2小分子抑制剂并探讨此类抑制剂的构效关系。方法 ·通过计算机辅助药物设计方法，以CDK2-cyclinA2晶体ATP结合区域为口袋，筛选出先导化合物。根据CDK2-cyclinA2的ATP结合区域特点，设计合成一系列苯磺酰胺类化合物；根据已构建好的体外激酶活性检测体系，对化合物体外活性进行研究。结果 ·合成了29个新型苯磺酰胺类CDK2-cyclinA2抑制剂，化合物对CDK2-cyclinA2抑制检测结果显示，WZ-026对CDK2-cyclinA2抑制作用的IC50值为3.81μmol/L。结论 ·综合虚拟筛选、化学合成、生物检测等方法，得到对CDK2-cyclinA2有明显抑制活性的苯环酰胺类化合物WZ-026；初步得到此类小分子化合物与CDK2-cyclinA2的作用模式。

关键词: CDK2-cyclinA2, 细胞周期, 抑制剂, 构效关系

Abstract:

Objective · To design and synthesize a series of benzenesulfonamide derivatives, test their inhibitory activity to CDK2-cyclinA2 kinase, and investigate the structure-activity relationship. Methods · Virtual screening was executed via computer-aided drug design according to the ATP binding site in CDK2-cyclinA2 protein crystal. A series of benzenesulfonamide derivatives were designed and synthesized on the basis of the interaction modes between the lead compound and the CDK2-cyclinA2. The biological evaluation of compounds was made through the CDK2-cyclinA2 in-vitro kinase activity detection system. Results · Twenty-nine new benzenesulfonamide compounds were prepared, and their inhibitory activity to CDK2-cyclinA2 was elicited. WZ-026 had the highest inhibitory parameter, which half maximal inhibitory concentration (IC50) was 3.81 μmol/L. Conclusion · By multipurpose utilization of virtual screening, chemical synthesis, and biological activity test, a benzenesulfonamide compound WZ-026 was found, which has great inhibitory activity towards CDK2-cyclinA2. Preliminary structure-activity relationship of compounds was obtained.

Key words: CDK2-cyclinA2, cell cycle, inhibitor, structure-activity relationship